Serum amyloid A (SAA) is an inflammatory marker that predicts cardiovascular disease events. SAA[unreadable] levels are elevated in the metabolic syndrome, which is characterized by a markedly increased risk for[unreadable] premature cardiovascular disease. We recently found that dietary cholesterol increases circulating SAA levels[unreadable] in mice and that circulating SAA levels predict atherosclerosis better than cholesterol levels.[unreadable] SAA circulates predominantly on high density lipoprotein (HDL). It is produced mainly by the liver,[unreadable] but also by extra-hepatic cells such as macrophages and vascular smooth muscle cells. SAA has[unreadable] proteoglycan-binding domains that can serve as bridges between lipoproteins and vascular proteoglycans.[unreadable] Apo A-I, the major apolipoprotein of HDL, is abundant in atherosclerotic lesions in both mice and humans,[unreadable] where it co-localizes with both SAA and proteoglycans. These observations suggest that retention of HDL by[unreadable] SAA in the vascular intima might inhibit the atheroprotective effects of HDL and play a role in atherogenesis.[unreadable] We propose that SAA is a mediator rather than a marker of atherosclerosis and that factors that[unreadable] increase circulating SAA levels, such as dietary cholesterol and the metabolic syndrome, might promote[unreadable] atherosclerosis by facilitating the binding of lipoproteins, including HDL, to vascular proteoglycans.[unreadable] Therefore, we plan to (1) further investigate the dietary and metabolic factors that regulate SAA levels[unreadable] in blood and to determine the impact of elevated SAA levels on atherosclerosis, (2) determine which isoforms[unreadable] of SAA are produced by vascular smooth muscle cells and macrophages and whether SAA produced by[unreadable] vascular cells contributes to circulating SAA, and (3) using both in vitro and techniques and mice models in[unreadable] which SAA is overexpressed, to establish whether SAA is a mediator rather than merely a marker of[unreadable] atherosclerosis.[unreadable] The proposed studies will provide important information about factors that regulate SAA levels in blood[unreadable] and predispose humans to cardiovascular disease. They will also establish whether SAA promotes HDL[unreadable] retention in the artery wall.